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> Pathway Inhibitors>Protein Inhibitors>TH7299

Protein Inhibitors

TH7299 View larger

TH7299

AOB10412

CAS: 1415648-20-2

 

Chemical Name: (4-(3-(4,6-Diamino-2-oxo-1,2-dihydropyridin-3-yl)ureido)benzoyl)-L-glutamic acid

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Quantity Discount Table - Order More To Get More Price Discount

QuantitymgUnit Price ($/mg or $/Unit)Final Price
15 $58.65 Total: $293.25
110 $49.68 Total: $496.80
125 $42.09 Total: $1,052.25
150 $35.88 Total: $1,794.00
1100 $31.05 Total: $3,105.00

Data sheet

Molecular FormulaC18H20N6O7
Molecular Weight432.39
CAS Numbers1415648-20-2
Storage Condition0°C (short term), -20°C (long term), desiccated
SolubilityDMSO
Purity98% by HPLC
SynonymTH 7299, TH-7299
IUPAC/Chemical Name(4-(3-(4,6-Diamino-2-oxo-1,2-dihydropyridin-3-yl)ureido)benzoyl)-L-glutamic acid
InChl KeyXYBHHWPTCKDMPA-NSHDSACASA-N
InChl CodeInChI=1S/C18H20N6O7/c19-10-7-12(20)23-16(28)14(10)24-18(31)21-9-3-1-8(2-4-9)15(27)22-11(17(29)30)5-6-13(25)26/h1-4,7,11H,5-6H2,(H,22,27)(H,25,26)(H,29,30)(H2,21,24,31)(H5,19,20,23,28)/t11-/m0/s1
SMILES CodeO=C(O)CC[C@@H](C(O)=O)NC(C1=CC=C(NC(NC2=C(N)C=C(N)NC2=O)=O)C=C1)=O
References1) Green AC, et al. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nat Metab. 2023 Apr;5(4):642-659. doi: 10.1038/s42255-023-00771-5. Epub 2023 Apr 3. PMID: 37012496; PMCID: PMC10132981.2) Bonagas, N., et al. Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress. Nat Cancer 3, 156–172 (2022). https://doi.org/10.1038/s43018-022-00331-y

More info

First-in-class MTHFD2 inhibitor, impairing cancer progression in vivo, preventing thymidine production leading to misincorporation of uracil into DNA and replication stress

Mechanism & Target Enzymes

  • TH7299 inhibits MTHFD2 (mitochondrial methylenetetrahydrofolate dehydrogenase 2), but it is not very selective: it also inhibits MTHFD2L (an isoform) and MTHFD1. 

  • Some reported potencies:

    EnzymeIC₅₀ for TH7299
    MTHFD2~ 254 nM PMC+2probechem.com+2
    MTHFD1~ 89 nM PMC+2probechem.com+2
    MTHFD2L~ 126 nM PMC+2probechem.com+2

  • Binding mode: TH7299 binds in the folate binding site of MTHFD2 / MTHFD2L. The structure of human MTHFD2L in complex with TH7299 has been solved (PDB 7QEI). Chemistry Europe+2RCSB PDB+2

  • Key interactions include hydrogen bonds between the diaminopyrimidine head group and residues like Asp169, Val145 / Leu147; interactions via the urea linker with Asn101, Lys102, Gln146; pi-stacking with Tyr98; the glutamate tail interacting with Gly324 and Tyr292; plus hydrophobic contacts. Chemistry Europe

Biological Effects & Potential Uses

  • In cellular assays (acute myeloid leukemia cells in vitro & in vivo), TH7299 (along with related inhibitors) causes:

    1. Reduced replication fork speed

    2. Replication stress

    3. S-phase cell cycle arrest

    4. Apoptosis (cell death) in some settings. PMC

  • It also leads to disruption of thymidine production, causing uracil misincorporation into DNA. These are hallmarks of perturbing folate-1C metabolism. PMC+1

  • As of now, TH7299 is for research use only; it is preclinical (not approved for human or veterinary use). 

Strengths & Limitations

Strengths:

  • Nanomolar potency against multiple folate pathway enzymes → can be useful as a tool compound for studying those pathways. PMC

  • Crystallographic data available → structure-guided drug design possible. RCSB PDB+1

Limitations:

  • Lack of high isoform selectivity: TH7299 also inhibits MTHFD1 and MTHFD2L, which may lead to off-target effects or toxicity in settings where those isoforms are essential. PMC+1

  • Lead times / supply may be long for some vendors; stock is sometimes unavailable.